- Vera Hassner Sharav,
President, and John H. Noble, Jr., Ph.D., steering committee member,
The Alliance for Human Research Protection (AHRP), before the Subcommittee
on Public Health, Committee on Health, Education, Labor, & Pensions,
United States Senate at Hearing, "Protecting Human Subjects
in Research: Are Current Safeguards Adequate?" on April 23,
2002.
- Witness Short Title. The Alliance for Human Research Protection (AHRP) is a national
network of lay people and professionals dedicated to advancing responsible
and ethical medical research practices, to ensure that the human
rights, dignity and welfare of human subjects are protected, and
to minimize the risks associated with such endeavors.
- We thank the Senate
Subcommittee on Public Health for this opportunity to present testimony
on current weaknesses and flaws in the regulatory and oversight
system for protecting the life safety and human rights of the child
subjects of biomedical research. The testimony explains how recent
government actions threaten to make a bad system worse.
IV. Minimal
Risk for Children.
Current federal
regulations set no limits on the level of risk that a competent adult
may voluntarily choose to undertake for the sake of science. The regulations
require prior approval by a review board (IRB) to ensure the research
meets scientific and ethical justification, to ensure that the risks
and benefits (if any) are fully disclosed to the subject, and that
the subject can exercise the right to give or withhold informed consent.
The regulations rely on trust that the research stakeholders - the
scientists, sponsors, and institutional review boards - will
comply with the regulations. That trust, however, has been betrayed
and even the nation's prestigious research centers were found in violation
of ethical standards, including informed consent.
Children present
us with the greatest ethical problem because they are not legally
competent to exercise informed consent or to protect themselves from
unwanted experiments that put them in harm's way. This status relegates
children to the category of involuntary human subjects.
Children's
dependency on others to decide what serves their best interest places
them at particular disadvantage. In 1983 special regulations (45 CFR
46 Subpart D, Sections 404-409) were adopted to protect children from
harm and to ensure that they will not be exploited in nontherapeutic
experiments involving greater than minimal risks or discomfort. Thus,
federal regulations protect children by requiring a higher standard
of justification for approval of pediatric research by setting limits
on the level of risk.
45 CFR 46.102
defines "minimal risk" for adults and children alike:
Minimal
risk means that the probability and magnitude of harm or discomfort
anticipated in the research are not greater in and of themselves
than those ordinarily encountered in daily life or during the performance
of routine physical or psychological examinations or tests.
Regulatory
protections were adopted to ensure that children, who are not volunteers,
are protected from undue harm under the provisions of 45 CFR 46.405
- Research involving greater than minimal risk but presenting
the prospect of direct benefit to the individual subjects.
Research under
Section 405 is permissible only if "the relation of the anticipated
benefit to the risk is at least as favorable to the subjects as that
presented by available alternative approaches."
When the research
offers no possibility of a direct benefit, i.e., is nontherapeutic,
the regulations restrict such research to "minimal risk."
If there is evidence that the research is of "vital importance
for the understanding of the subjects' disorder or condition"
then the regulations permit children to be subjected to "a minor
increase over minimal risk."
45 CFR 46
Section 406 - Research involving greater than minimal risk and
no prospect of direct benefit to individual subjects, but likely
to yield generalizable knowledge about the subject's disorder or
condition.
Under Section
46.406 research could be conducted only if:
- . . . the risk
represents a minor increase over minimal risk; the intervention
or procedure presents experiences to subjects that are reasonably
commensurate with those inherent in their actual or expected
medical, dental, psychological, social, or educational situations;
- . . . the intervention
or procedure is likely to yield generalizable knowledge about
the subjects' disorder or condition which is of vital importance
for the understanding or amelioration of the subjects' disorder
or condition. [Emphases added]
However, the
1997 FDA Modernization Act (FDAMA) offered the pharmaceutical industry
enormous financial incentives - i.e., a six-month patent exclusivity
extension - if they tested their patented drugs on children. FDAMA
was passed without any risk assessment by the FDA or NIH, and without
Congress being informed about the potential unintended consequences
that could result unless additional protections were enacted for children.
As a result, children who are legally precluded from exercising the
right to refuse are being aggressively recruited to bear the burden
of testing drugs that may (or may not) be in their best interest.
The law, unfortunately, failed to balance financial incentives with
new (or improved) safeguards to protect an increased number of young
children being exposed to the hazards of research.
In 2001 Alice Dembner
of the Boston Globe examined research conducted since 1994 that
involved children. She reported (in a series of articles) that children
had suffered and died in clinical trials in which ethical standards
had been violated.[1]
Financial incentives for parents, physicians, and researchers are
undermining children's welfare. Children are being recruited with
Toys 'R Us gift certificates. Parents in need of money are offered
as much as $1,000 to "volunteer" their children for drug
experiments that involve risks of harm.[2]
The physicians who are engaged in such coercion receive as much
as $5,000 referral fees (kickbacks) for the
recruitment of children.[3] In the last seven years alone, according
to Dembner, at least eight children died in medical experiments
and hundreds suffered harmful side effects.
The number of child research subjects has grown from about 16,000
in 1997 to about 45,000 in 2001, and "there is strong reason
to believe that deaths and injuries in research involving children
are more widespread" than available statistics would indicate.
[4]
The FDA acknowledged that before FDAMA the use of children as subjects
in phase I safety drug studies "had been primarily limited
to life threatening diseases and children who had the disease"
in question.[5]
The policy prior to FDAMA protected children from harmful experiments
in accord with the 1983 federal regulations (45 CFR 46.404-409).
Following passage of FDAMA, however, federal policy broadened the
criteria for inclusion of children in research generally and for
participation of children entered in high-risk experiments. In 1999
the FDA acknowledged that the post-FDAMA policy change "led
to an increasing number of proposals for studies of safety
and pharmacokinetics, including those in children who do not have
the condition for which the drug is intended."[6]
One can only speculate
about the negative impact this policy change had on the healthy
children who had been subjected to drug trials before the FDA rescinded
the policy. FDA Associate Director of Pediatrics, Dr. Dianne Murphy,
was reported to have stated at a conference (April 3, 2001): "FDA
will no longer accept information submitted to the agency for pediatric
exclusivity if the data is derived from children who are not patients
and for whom there is no foreseeable benefit." [7] The same report, however, indicated
the FDA was "upset that pharmaceutical companies are continuing
to enroll healthy children in clinical trials."
V. Implementation
of 45 CFR 46, Section 407
45 CFR 46, Section
407 - Research not otherwise approvable which presents an opportunity
to understand, prevent, or alleviate a serious problem affecting
the health or welfare of children.
Section 407 requires
nontherapeutic research involving greater than minimal risk and
no potential benefit for the child subjects to be reviewed by the
Secretary of Health and Human Services and approved only after consultation
with a panel of appropriate experts and "following opportunity
for public review and comment." This procedure in many respects
parallels the process of initiating or changing regulations that
is prescribed by the Administrative Rulemaking Act because of the
gravitas of the issue.
The Department of Health
and Human Services (DHHS), through its Office of Human Research
Protections (OHRP), assisted by the National Human Research Protection
Advisory Committee (NHRPAC), and its Food and Drug Administration
(FDA) Pediatric Advisory Committee have embarked on initiatives
to broaden the recruitment of children - even healthy children -
for clinical trials that may undermine their health and welfare.
Indeed, in one
2000 DHHS draft policy and procedure document healthy children who
are to be recruited for clinical trials are referred to as "risk-bearing
normal control subjects."[8] The FDA's Pediatric
Advisory Subcommittee (PAS) acknowledged: "pediatric studies should be conducted in subjects who may
benefit from participation in the trial. Usually this implies the
subject has or is susceptible to the disease under study."
However, the PAS concluded that by reference to a broad definition
of potential benefit, "any child has the potential to
benefit from a treatment for otitis media" (middle ear infection).[9]
These OHRP and FDA
advisory committees are declaring normal stages of child development
as if they were preludes to pathology: "prematurity, infancy,
adolescence, poverty, living in a compromised physical environment,
and institutionalization" are declared to be "disorders
or conditions in children that warrant permissible research that
presents greater than minimal risk without a prospect of direct
benefit to the child."[10]
The regulatory protections
children have had since
1983 are being dismantled one section at a time. Federal policy
is overturning regulatory prohibitions without issuing an advanced
notice for proposed rulemaking changes (ANPRM) as required under
the Administrative Rulemaking Act. Instead, a backdoor strategy
is being pursued that redefines regulatory terms and protective
restrictions in order to legitimize currently prohibited risky and
painful experiments on young children.
Those
arguing that all children are potentially "at risk" of
a future condition attempt to justify the inclusion of all children
- be they healthy or critically ill - in experiments that expose
them to pain and risks of harm even when there was no potential
for an immediate direct benefit. By applying a broad standard to
the definition of "potential benefit" in this way, children
are being deprived of existing, more protective federal regulations
under 45 CFR 46, Subpart D. The new policy would open access to
children who do not have a bone fide condition as research subjects
in experiments that would cause them pain and put them at risk of
harm without a potential foreseeable benefit. Children are being
recruited to test drugs whose safety is uncertain. Small children
are subjected to discomfort and foreseeable risks of harm on the
basis of a presumed potential risk for which there is no empirical
evidence.[11]
Dr. Benedetto Vitiello,
NIMH's Director of Child and Adolescent Treatment and Preventive
Interventions Research Branch, provided confirmatory evidence in
this regard when stating "pediatric psychopharmacology has
recently seen an unprecedented expansion . . . NIMH-funded research
for clinical trials in youths has more than doubled in the last
few years."[12]
At the same time he acknowledges this is happening despite the existence
of "diagnostic uncertainty surrounding most manifestations
of psychopathology in early childhood." Dr. Vitiello also reveals
"only limited data exist on the efficacy and safety of antidepressants
and mood stabilizers in school-age prepubertal children. Clinical
trials of these agents in preschoolers do not seem possible given
the current uncertainties about diagnostic validity of mood disorders
in children <6 years old."[13] Despite the public
expression of serious misgivings by one of its officials, NIMH has
embarked upon a highly controversial psychotropic drug experiment
on preschool children - Preschool ADHD Treatment Study (PATS) -
in which some of the children being recruited are as young as three
years old.[14] Their parents are being seduced
with financial incentives beyond travel expenses‑‑$645
- if the child completes the study.[15]
The Alliance for Human
Research Protection (AHRP) believes that financial inducements of
this size offered to vulnerable and easily exploitable poor parents
are inherently coercive. It believes recent efforts to evade ANPRM
and the Administrative Rulemaking Act are calculated to sanction
the exploitation of children and thereby increase the profits of
big business.[16]
A six-month extension for Prozac, for example, can mean an additional
$831 million for Eli Lilly.[17] What chance does a poor kid have
against marketplace dynamics of such magnitude?
VI. Are these trials
ethical?
Gage
Stevens is a tragic example of the consequences of using babies
to test drugs.[18]
In 1999 Propulsid's sales reached $950 million, while its death
rate - according to the FDA - had reached 80, including both adults
and children.[19]
Yet, nine month old Gage Stevens was recruited into an FDA-approved
clinical trial and given Propulsid and Tagament for four months.
He died of cardiac arrhythmia - as had six-month-old Chase Brown
the year before. By the time it was taken off the market, nineteen
children who had been given Propulsid had died. The Pittsburgh Children's
Hospital consent forms signed by the parents of children in the
Propulsid experiments stated the FDA had approved Propulsid for
use in children.[20] It was a false claim and one used to facilitate
the testing of Propulsid on children. After his death, Gage Stevens'
parents said, "Little did we know that Gage was basically a
guinea pig, and they never told us that [Propulsid] causes dangerous
side effects, or there had been deaths."[21]
The final blow was delivered when the baby's parents learned from
the autopsy report that his esophagus "failed to show signs
of significant inflammation or other hallmarks of gastroesophageal
reflux."[22] In other words, the baby didn't
have the condition for which he was used in the clinical trial.
The antipsychotic drug,
Zyprexa, was approved for schizophrenia in adults. Its side effect
profile is so severe that the FDA approved the drug for short-term
use only in bi-polar patients.[23]
Yet five children aged six to eleven were recruited for clinical
trials of the drug. According to their published report, investigators
at the University of California-Los Angeles, tested Zyprexa on children
who were not even diagnosed as having schizophrenia; they were diagnosed
as having a variety of other questionable psychiatric disorders,
including ADHD,[24]
a condition whose diagnostic validity has never been established.[25]
According to the published report, all the children
in the UCLA trial who were given Zyprexa experienced adverse effects,
including sedation, weight gains of up to 16 pounds, and akathisia.
Further, none of the children were helped by the drug, and the trial
was terminated less than six weeks after it had begun.
Since nothing in the
published report provides a medical justification for prescribing
a powerful antipsychotic drug that exposed these young children
to serious risks, the trial seems to have been conducted for other
reasons. It seems likely that the decision to test Zyprexa in children
was influenced by the powerful incentive of a possible six-month
patent extension under FDAMA. In 1998 Zyprexa sales in the U.S.
were $1 billion; in 2000, $2 billion; and in 2001 Zyprexa topped
Prozac sales at $3 billion.[26]
Clearly, a six-month patent extension is enormously profitable and
provides a powerful incentive to test every conceivable drug on
children.
No doubt, the researchers
and IRBs at the Kennedy Krieger Institute, who saw nothing wrong
with approving an experiment that would expose healthy babies and
toddlers to lead poison, regarded those children as "risk bearing
subjects." The purpose of the experiment was to determine the
effectiveness of varying degrees of lead paint abatement.[27]
During the experiment, the level of lead in the children's blood
was allowed to rise to hazardous levels. Researchers drew blood
samples from the children, recorded the rise in lead poisoning,
and did nothing to intervene. Fortunately, Maryland's highest court
(the Maryland Court of Appeals) issued a resounding ruling on behalf
of children everywhere when it condemned this experiment and all
nontherapeutic experiments that expose children to any but minimal
risks.[28]
The Court cited international codes of ethics - the Nuremberg code
and the Declaration of Helsinki - and federal regulations that affirmed
the primacy of individual rights:
Whatever the interests
of a parent, and whatever the interests of the general public
in fostering research that might, according to a researcher's
hypothesis, be for the good of all children, this court's concern
for the particular childover-arches all other interests. It is,
simply, and we hope, succinctly put, not in the best interest
of any healthy child to be intentionally put in a nontherapeutic
situation where his or her health may be impaired, in order to
test methods that may ultimately benefit all children. [p.
80]
At the April 29, 2002
NHRPAC meeting, a report will be presented by its children's workgroup,
to which the AHRP President, Ms. Vera Hassner Sharav, will submit
a dissenting opinion. The workgroup panel of experts - like most
advisory panels - represent the interests of research institutions
insofar as they are all affiliated with research centers or agencies
that receive funding from the pharmaceutical industry and government.
The panel claims that healthy children - who would not legitimately
be subjected to nontherapeutic research under 45 CFR 46, Section
406 - may have a genetic predisposition which puts them "at
risk" of assumed, unverified conditions (that may or may not
develop). It is claimed that such vaguely defined speculative risks
"warrant permissible research that presents levels of risk
that are a minor increase over minimal without prospect of direct
benefit." The assumption of genetic predisposition is invalid
insofar as it is not based on scientific evidence - merely speculation.
As the neuroblastoma case demonstrates,[29]
there is a possibility that more harm than good will be done and,
therefore, the risks are not justified. In that case a screening
test producing largely false-positive findings resulted in unnecessary
surgery on thousands of Japanese babies.
The Alliance for Human
Research Protection (AHRP) believes that the pain and risks of harm
in a growing number of experiments that offer no personal benefit
are against the best interest of children.[30]
Children are being recruited for speculative experiments whose value
is questionable.[31] Indeed, a most telling observation in this regard
is found in the 1994 report of the Advisory Commission on Human
Radiation Experiments (ACHRE):
Many
experiments that prove to be of little value in the advance of medical
knowledge are, at the time they are implemented, well designed and
appropriate attempts to address important research questions.
If the standard of permissible
research is left to the judgment of the biomedical research community
without the participation of community members whose moral standards
are likely to differ from theirs, children will be unjustifiably
exposed to harmful experiments. The evidence, then and now, confirms
the judgment by the Maryland Court of Appeals, which stated:
[I]t is clear
to this court that the scientific and medical communities cannot
be permitted to assume sole authority to determine ultimately
what is right and appropriate in respect to research projects
involving young children. [p. 80]
Whereas the courts have
unequivocally ruled that absent a benefit for the child involved,
nontherapeutic research that posed greater than minimal risk was
repugnant and violated the moral standards of the community.[32]
Advisory panels convened by DHHS are now attempting to legitimize
those very experiments through disingenuous linguistic tinkering.
The attempt to broaden the interpretation of "minimal
risk" and "a minor increase over minimal risk"
will result in children being subjected to a higher threshold of
pain and risks of harm greater than what current federal regulations
permit.[33]
Physicians whom the Alliance
for Human Research Protection (AHRP) has consulted have indicated
that the designated risk categories recommended by the NHRPAC workgroup
for invasive and, in some cases, exceedingly painful procedures,
are astounding in their disregard for the welfare of children. Among
the procedures designated as "minimal risk" are venipuncture,
the glucose tolerance test, the indwelling heparin lock catheter,
chest x-ray, and bone-density and bone-wrist x-ray. An indwelling
heparin catheter is not something that a healthy child would experience,
and venipuncture does pose risk of infection as does the glucose
tolerance test. Single x-ray radiation exposure presents a small
but cumulative risk of cancer.[34]
Because the magnitude of the risk is unknown and the impossibility
of predicting the lifetime exposure for a particular child, it cannot
be asserted that these procedures expose a child to "minimal
risk." Indeed, the MEDLINE PLUS Encyclopedia states: "There
is a general agreement that routine chest X-rays should not be done
on healthy people for screening purposes. There is little benefit
of a chest X-ray in screening smokers who have no symptoms."[35]
The following exceedingly
painful procedures involve measurable risks and require informed
consent when used in standard clinical practice. How then can one
justify classifying the following procedures as merely "a minor
increase over minimal risk" when children would be subjected
to the pain and risks?
Lumbar puncture,[36] skin punch biopsy,[37] bone marrow aspirate,[38] nasogastric tube insertion, and
uretha catherization are not procedures expected in the life of
a healthy child. Tympanocentesis, which the workgroup regards as
"generally minor increase over minimal risk" is an extremely
painful surgical procedure involving the insertion of a needle through
the ear drum to drain the ear of infectious matter. The American
Academy of Pediatrics indicates "the patient must be completely
immobile while the needle is inserted through the tympanic membrane.
A papoose board or a sheet can be used to immobilize the body. An
extra attendant is required to hold the patient's head steady"
[39]
It is hard to imagine
that researchers from prestigious universities would volunteer their
children for these procedures for the sake of science.
If adopted, the workgroup
recommendations would lift the restrictions that currently provide
children with some protection from unwanted experimentation. The
draft fails to provide any guidance that would ensure compliance
with the protective standards provided in the regulations - as though
these were not major problems.
Last,
the Alliance for Human Research Protection (AHRP) is concerned about
the secrecy that surrounds implementation of the very Section 407
provisions that require public transparency. Recall that Section
407 requires nontherapeutic research involving greater than
minimal risk and no potential benefit for the child subjects to
be reviewed by the Secretary of Health and Human Services, by a
panel of experts, and the public before it could be approved. On
February 7, 2002, we requested (1) copies of current research proposals
for which requests have been received for review by a HHS Secretarial
panel of experts under 45 CFR 46 Subpart D, Section 407; and (2)
the list of experts convened by the Sec for the purpose of advising
him regarding these proposals.
We
received the reply on March 29, 2002, from Ms. Darlene Christian,
Public Health Service FOIA Officer, that currently seven protocols
are pending for expert review under the provisions of Section 407
- not 26 - as stated by Dr. Greg Koski at the NHRPAC meeting on
January 28, 2002, and that all seven have been reviewed by experts,
but none have yet resulted in final determinations. How many are
there really - seven or 26? The reply went on to say:
Release
of information, at this stage, would interfere with the agency's
deliberative and decision-making processes. Further, each researcher
has commercial and privacy interest in release of any information
that would identify the researcher or the research prior to a funding
decision. Therefore, at this time, I must deny you full access to
these records.
With
respect to your request for a list of experts, there is no fixed
panel of experts for review under Sec 407. Panels of experts are
formed for reviews dependent on the needs of each protocol. Release
of expert identities associated with the review of individual protocols
would interfere with the agency's deliberative and decision-making
processes and have a chilling effect on the ability of the agency
to obtain frank and candid opinions from its reviewers. Accordingly,
I must deny you access to the identities of the individuals who
performed such reviews.
We
leave the Senate Subcommittee on Public Health with this question
to ponder, "How can the public ever obtain sufficient knowledge
on which to provide the Secretary of HHS input pursuant to Section
407 requirements if "commercial and privacy interests"
are allowed to trump access to needed information?" In a field
rife with conflicts of interests, is it the expectation of the U.S.
Congress that citizens receive only such information as government
officials deem acceptable for their consumption?
The
Alliance for Human Research Protection (AHRP) is hopeful that this
is not the intent of the U.S. Congress; indeed, we hope the U.S.
Congress will affirm that no barriers will be permitted to come
between citizens and information needed to protect against potential
harm. In our view, no research protocol can be legitimately processed
under Section 407 provisions without full disclosure of all
relevant information, including that which some petitioners may
perceive to ill serve their "commercial and privacy interests."
Citizens resent being patronized and manipulated by those appointed
to faithfully discharge the requirements of law and regulation.
VII. Recommendation
The Alliance for Human
Research Protection (AHRP) suggests that a recommendation in the
original regulations proposed in 1973 for the protection of children
should be adopted. These proposed regulations reflected greater
sensitivity to the history of research abuses and the vulnerability
of children. They would have required review by a "Protection
Committee" in addition to review by an IRB. The Protection
Committee was to serve as the child subjects' advocates, monitoring
their selection, assessing the reasonableness of their parents'
consent, and monitoring their continued willingness to participate
in the research.[40]
Clinical research in
today's climate of corporate expediency is driven by financial interests
that conflict with the best interests of the child. Some parents
are too-easily swayed by financial incentives and too-quick to give
permission to conduct research on a child - especially if they are
poor and educationally disadvantaged. The recent flip-flopping of
the U.S. Department of Health and Human Services about implementation
of the so-called FDA Pediatric Rule poses a large threat to children's
health, safety and dignity.[41] We
sincerely hope the Senate Subcommittee on Public Health will insist
on proper safeguards for the protection of children's life safety
and human rights, asking the question, "Whose children will
be used as test subjects?"
f[3]See Dembner, "Teddy Bears" and "Dangerous Dosage"
(Ref. 1)
[5]FDA Center for Drug Evaluation and Research, Pediatric
Advisory Subcommittee. (1999, Nov. 5). Ethics Presentation Online.
Ethical issues in pediatric pharmaceutical research where there
is no primary intention of direct benefit. Online at: http://www.fda.gov/cder/pediatric/pedethics-1199.htm
[6]See FDA Center for Drug Evaluation and Research, Pediatric
Advisory Subcommittee (1999, Nov. 5). Ethics Presentation Online.
Ethical issues in pediatric pharmaceutical research where there
is no primary intention of direct benefit. Online at: http://www.fda.gov/cder/pediatric/pedethics-1199.htm
[7]Inside Washington (2001, April 6). FDA Week.
[8]See DRAFT Policy and Procedures for DHHS Research Involving
Children - 45 CFR 46.407, last revised 3-12-01. Distributed by the
Office of Human Research Protections (OHRP), March 16, 2000. Dissenting
comments were submitted by Vera Hassner Sharav and Dr. Marie M.
Cassidy, late Professor of Physiology, George Washington University
School of Medicine, to OHRP, April 5, 2001, under the corporate
name CIRCARE.
[9]FDA Center for Drug Evaluation and Research, Pediatric
Advisory Subcommittee (1999, Nov. 5). Ethics Presentation Online.
Ethical issues in pediatric pharmaceutical research where there
is no primary intention of direct benefit. Online at: http://www.fda.gov/cder/pediatric/pedethics-1199.htm
See
also FDA Center for Drug Evaluation and Research, Pediatric Information.
FDA Ethics Working Group Consensus Statement on the Pediatric Advisory
Subcommittee's November 15, 1999 Meeting; Final, April 19, 2000.
Online at: http://www.fda.gov/cder/pediatric/ethics-statement.htm
[10]Children's Workgroup of the National Human Research
Protection Advisory Committee to DHHS Report, April 2002.
[11]"Uncertainty about the diagnosis of mental disorder
in preschoolers has precluded FDA from requesting studies of psychoactives
in younger children," according to Vitiello, B. (2001). Psychopharmacology
for young children: Clinical needs and research opportunities. Pediatrics,
108: 983-990.
[14]PATS, a collaborative, six-site, randomized clinical
trial (to be conducted September, 2000 -August, 2003), was launched
as "New Frontiers in Pediatric Psychopharmacology" at
the 47th annual meeting of the American Academy of Child and Adolescent
Psychiatry, held at the Hilton-New York in New York City, October
24 - 29, 2000. PATS trials will be conducted at Columbia University,
Duke University, Johns Hopkins University, New York University,
and the University of California campuses at Los Angeles and Irvine.
[15]The Alliance for Human Research Protection (AHRP) has
obtained a copy of the NIMH Preschool ADHD Treatment Study (PATS)
protocol under the Freedom of Information Act.
[17]See Zimmerman, R. (2001, Feb. 5). Drug makers find a
windfall testing adult drugs on kids. Wall Street Journal: Front
page.
[18]Reuters Health Information Services, Inc. (1998). FDA
issues warning of cardiac problems with J&J's Propulsid. Online
at: http://www.heartinfo.org/news98/propulsid71698.htm
Among
the warnings issued by Janssen Pharmaceutica to physicians was:
Pediatric
Use: Safety and effectivenesss in pediatric patients have not been
established. Although causality has not been established, serious
adverse
events, including death, have been reported in infants and children
treated
with cisapride. Several pediatric deaths were due to cardiovascular
events
(third degree heart block and ventricular tachycardia). Pediatric
deaths have
been associated with seizures and there has been at least one case
of
sudden unexplained death' in a 3-month-old infant. (Janssen Pharmaceutica
"Dear
Doctor" letter, June 26, 1998.)
See
also Willman D. (2000, Dec. 20). Propulsid: A heartburn drug, now
linked to children's deaths. Los Angeles Times: Front page. Online
at: http://www.pulitzer.org/year/2001/investigative-reporting/works/willman2.html.
See also Neergaard, L. (2000, Feb. 7). Is Propulsid safe for babies?
Associated Press. Online at: http://onhealth.webmd.com/baby/briefs/reuters/item%2C79331.asp.
[21]See Mazo, Ref 20, and Neergaard, L. (2000, Feb. 15).
A warning for tiny hearts: Safety of heartburn drug Propulsid in
question. Pittsburgh Post-Gazette.
[24]See Krishnamoorthy, J. and King, B.H. (1998). Open-label
olanzapine treatment in five preadolescent children. Journal of
Child and Adolescent Psychopharmacology, 8:107-13.
[25]In 1998, NIH convened a panel
of experts to reach a consensus about the diagnosis and treatment
of AHDD. In its final statement the NIH consensus panel acknowledged:
The risks of treatment,
particularly the use of stimulant medication, are
of considerable interest. Substantial evidence exists of wide variations
in the use of psychostimulants across communities and physicians,
suggesting no consensus among practitioners regarding which
ADHD patients should be treated with psychostimulants. However,
there is no evidence regarding the appropriate ADHD diagnostic
threshold above which the benefits of psychostimulant therapy
outweigh the risks Finally, after years of clinical research
and experience with ADHD, our knowledge about the cause
or causes of ADHD remains largely speculative. Consequently, we
have no documented strategies for the prevention of ADHD. See Diagnosis
and Treatment of Attention Deficit Hyperactivity Disorder. NIH
Consensus Statement, November 16-18, 1998. Online at: http://odp.od.nih.gov/consensus/cons/110/110_statement.htm
[30]Examples of cases within the last 5 years in which children
suffered harm in clinical trials:
Castellanos,
F.X. et al. (1996). Cerebrospinal fluid homovanillic acid predicts
behavioral response to stimulants in 45 boys with ADHD. Neuropsychopharmacology,
14: 125-137;
Moss,
M. (1996, June 12). A U.S. experiment on young children ignites
painful debate. Wall Street Journal: Front page.
Willman,
D. (2000, Dec. 20). Propulsid: A heartburn drug now linked to children's
deaths. Los Angeles Times: Front page. Online at: http://www.pulitzer.org/year/2001/investigative-reporting/works/willman2.html
Mazo,
E. (2000, April 27). Infant's death raises alarms on who's used
in drug trials. Pittsburgh Post-Gazette. Online at http://www.post-gazette.com/healthscience/20000427propulsid1.asp;
Note:
The FDA and the IRB at Children's Hospital (Pittsburgh) approved
a protocol that required some babies to be given a deadly combination
- Propulsid and Tagamet - despite the fact that in Canada the drug
label warned physicians that there is a contraindication in the
use of Tagamet and Propulsid together.
Spice,
B., Science Editor (2000, July 9). Was baby treated for ailment
he didn't have? Pittsburgh Post-Gazette. Online at: http://www.post-gazette.com/healthscience/20010709gage0709p5.asp
Dembner
A. (2001, March 20). Teddy bears and veiled threats. Boston Globe:
C-1. Online at: http://199.97.97.16/contWriter/yhd7/2001/03/21/medic/4904-0206-pat_nytimes.html
Marshall, E. (2000, Nov. 17). Planned Ritalin trial for tots heads
into uncharted waters. Science, 290: 1280-81.
Lambert,
N.M. (1998). Stimulant treatment as a risk factor for nicotine use
and substance abuse. NIMH Consensus Conference. Online at: http://www.add.about.com/health/add/library/weekly/aa1119v.htm
Dembner,
A. (2001, March 25). Who's protecting the children? Drug research
raises concerns about policy and penalties. Boston Globe: Front
page. Online at: http://www.boston.com/dailyglobe2/084/nation/Who_s_protecting_the_children_+.shtml
Lemonick,
M.D. and Goldstein, A. (2002, April 14). At your own risk: Human
guinea pigs. Time Magazine: Cover story. Online at: http://www.time.com/time/covers/1101020422/story.html
[31]Silverman, W. (2000). Bad science
and the role of institutional review boards. Archives of Pediatric
Adolescent Medicine, 154: 1183-84; Dr. Marcia Angell, former editor
of The New England Journal of Medicine, was quoted by Lemonick and
Goldstein [Ref. 30] as sharing this view: "We have floods of
me-too drugs. So much research is trivial duplication."
[32]Maryland Court of Appeals, see Ref. 28: "Children,
it should be noted, are not in our society the equivalent of rats,
hamsters, monkeys and the like It is not in the best interest of
a specific child, in a nontherapeutic research project, to be placed
in a research environment which might possibly be, or which proves
to be, hazardous to the health of the child." [p. 79]
[33]At
the FDA Pediatric Advisory Subcommittee's deliberations (Nov 5,
1999) it was suggested that the regulatory definition of "minimal
risk" ("probability and magnitude of harm encountered
in everyday life") does not exclude death - "a risk of
everyday life includes death." It would appear that
at least some members on that Subcommittee consider death to be
"minimal risk" for research purposes. See Ref. 9.
[34]For
description of procedures and risks, see MEDLINE PLUS Encyclopedia.
Online at: http://www.nlm.nih.gov/medlineplus/ency/article/003337.htm
It states: "During a single radiograph, a small fraction of
the X-rays pass right through the body. The remaining photons are
absorbed by tissues in the body. The energy of the absorbed photons
can break apart, or ionize, compounds which may cause cell damage. Most
cell damage is soon repaired, however, some is permanent. For the
exposures encountered in conventional radiography, the risk of cancer
or heritable defects (via damaged ovarian cells or sperm cells)
is very low." The Encyclopedia further states: "Young
children and a developing fetus carried by pregnant women are
more sensitive to the risks of X-rays. Women should tell
health care providers about suspected pregnancy."
[36]Risks
of lumbar puncture include: Hypersensitivity (allergic) reaction
to the anesthetic; Discomfort during the test; Headache after the
test; Bleeding into the spinal canal; Brain herniation (if performed
on a person with increased intracranial pressure) resulting in brain
damage or death; Damage to the spinal cord (particularly if the
person moves during the test); Cisternal puncture or ventricular
puncture carry additional risk of damage to the brainstem or brain
tissue and risk of bleeding within the brain resulting in incapacitation
or death. See MEDLINE PLUS Encyclopedia.
[37]MEDLINE PLUS Encyclopedia: "In
a punch biopsy, a small cylinder of skin is removed. A local anesthetic
is injected. The skin around the biopsy site is pulled tight and
a punch (a hollow instrument) is firmly introduced into the skin
and rotated to obtain a sample; then the punch is removed. If a
large sample is taken, the area may be closed with stitches. Risks:
There is a chance of infection. If you tend to form large scars
(keloids) in response to a skin injury, there
is a fair chance one will form over the biopsy area. You may lose
a very small amount of blood during the procedure."
[38]Bone marrow aspirate: The site of puncture will be cleansed
with an antiseptic solution, and you will be given a local anesthetic
at the area. The site may be the pelvic bone or the breastbone.
Pain: There will be a prick and a slight burning sensation with
the local anesthetic. Pressure may be felt as the needle is inserted
into the bone. There is a sharp sucking sensation as the marrow
is aspirated, which lasts for only a few moments. MEDLINE PLUS Encyclopedia.
[39]
The American Academy of Pediatrics provides the following online
guideline for performing
Tympanocentesis to treat otitis media (ear infection) at: http://www.aap.org/otitismedia/www/vc/ear/case6/tcts.cfm
"Technique
of tympanocentesis: In the conditions mentioned, the pain associated
with tympanocentesis is only slightly greater than the pain that
already exists from acute inflammation of the tympanic membrane.
Therefore, no premedication is generally indicated."
"Site:
With an open-headed operating otoscope, the operator carefully selects
a target. This is generally in the posteroinferior quadrant. This
site prevents disruption of the ossicles during the procedure. While
it is easiest to use a trap to collect the fluid, an alternative
would be an 8.8-cm spinal needle (No. 18 or No. 20) with a short
bevel attached to a 1 ml syringe. The plunger is removed from the
syringe, a 3-way stop cock is inserted into the open end of the
syringe and a suction tube is placed over the stopcock opening.
The spinal needle is bent at a slight angle so that its end is out
of the operator's line of vision. The operator moves the needle
toward the posteroinferior quadrant, inserting it through the tympanic
membrane, and aspirates the middle ear effusion into the syringe."
Online at: http://www.aap.org/otitismedia/www/vc/ear/case6/tcts.cfm
[40]See 28 Fed. Reg. 31, 738 (1973); and Glantz, L.
(1998). Research with children. Amer. J. Law & Med., 26: 229-230,
Ref. 194.
[41]See FDA Press Office (2002, April 19). HHS RELEASE -
NEW PEDIATRIC DRUG SAFETY INITIATIVE.
